According to the NIH, 20.5 million Americans suffer from autoimmune diseases. Additionally, inflammation contributes potently to the progression and pathology of some age-related diseases, such as Alzheimer's disease, atherosclerosis and type 2 diabetes. Severe inflammatory diseases are treated by blocking the pro-inflammatory pathways, such as TNF receptor signaling, using biological drugs. But the clinical outcome is often uncertain and plagued by significant adverse effects. Characterization of novel regulators of these inflammatory pathways that are druggable, by more affordable small molecules is therefore of clinical and economic significance. The function of TRP channels, an exciting class of drug targets, in inflammation remains undefined. TRPM7, a TRP channel that contains a cation-conducting pore and a kinase domain, is highly expressed in the immune cells. By generating mouse lines with global and tissue-specific deletion of Trpm7, we discovered a crucial role for TRPM7 in the immune system, and now, we have uncovered a striking role for TRPM7 in macrophage activation, an essential checkpoint in inflammation. Our central hypothesis is that: Caspase-mediated proteolytic regulation of TRPM7 is essential for inflammatory signaling in macrophages.
Our specific aims are: (1) Define the regulation of TRPM7 by inflammatory caspases in macrophages; (2) Define the function of TRPM7 during Fas and TLR4 signaling in macrophages. Defining how caspase-mediated cleavage of TRPM7 controls Fas and TLR4 signaling during macrophage activation will advance TRPM7 as a molecular target in inflammatory diseases. Integration of multidisciplinary approaches, novel mouse lines and innovative molecular reagents uniquely position us to fill this gap of broad significance to inflammatory diseases in humans.

Public Health Relevance

According to the NIH, 20.5 million Americans suffer from autoimmune diseases. Additionally, inflammation contributes potently to the progression and pathology of some age-related diseases, such as Alzheimer's disease, atherosclerosis and type 2 diabetes. Severe inflammatory diseases are treated by blocking the pro-inflammatory pathways, such as TNF receptor signaling, using biological drugs. But the clinical outcome is often uncertain and plagued by significant adverse effects. Characterization of novel regulators of these inflammatory pathways that are 'druggable', by more affordable small molecules is therefore of clinical and economic significance. The function of TRP channels, an exciting class of drug targets, in inflammation remains undefined. TRPM7, a TRP channel that contains a cation-conducting pore and a kinase domain, is highly expressed in the immune cells. By generating mouse lines with global and tissue-specific deletion of Trpm7, we discovered a crucial role for TRPM7 in the immune system, and now, we have uncovered a striking role for TRPM7 in macrophage activation, an essential checkpoint in inflammation. Our central hypothesis is that: Caspase-mediated proteolytic regulation of TRPM7 is essential for inflammatory signaling in macrophages. Our specific aims are: (1) Define the regulation of TRPM7 by inflammatory caspases in macrophages; (2) Define the function of TRPM7 during Fas and TLR4 signaling in macrophages. Defining how caspase-mediated cleavage of TRPM7 controls Fas and TLR4 signaling during macrophage activation will advance TRPM7 as a molecular target in inflammatory diseases. Integration of multidisciplinary approaches, novel mouse lines and innovative molecular reagents uniquely position us to fill this gap of broad significance to inflammatory diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM108989-05
Application #
9836860
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Dunsmore, Sarah
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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